CA2987019C - Pyrido[3,4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof - Google Patents
Pyrido[3,4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof Download PDFInfo
- Publication number
- CA2987019C CA2987019C CA2987019A CA2987019A CA2987019C CA 2987019 C CA2987019 C CA 2987019C CA 2987019 A CA2987019 A CA 2987019A CA 2987019 A CA2987019 A CA 2987019A CA 2987019 C CA2987019 C CA 2987019C
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- CA
- Canada
- Prior art keywords
- pyrido
- zero
- pyrimidin
- amino
- piperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003839 salts Chemical class 0.000 title claims abstract description 68
- 159000000016 pyrido[3,4-d]pyrimidines Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 547
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- 230000002401 inhibitory effect Effects 0.000 claims abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 130
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 112
- -1 -OH Chemical group 0.000 claims description 71
- 125000001153 fluoro group Chemical group F* 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- TWFXSDGKDLLPFZ-UHFFFAOYSA-N pyrido[3,4-d]pyrimidine-2,8-diamine Chemical compound N1=C(N=CC2=C1C(=NC=C2)N)N TWFXSDGKDLLPFZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 11
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- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 11
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
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- 239000011593 sulfur Chemical group 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
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- 239000011737 fluorine Substances 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
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- 125000002993 cycloalkylene group Chemical group 0.000 claims description 5
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- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- FQWQZEXQOXIWIG-CYBMUJFWSA-N (1R)-1-[2-[(6-piperazin-1-ylpyridazin-3-yl)amino]-8-(propan-2-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol Chemical compound C(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC=1N=NC(=CC=1)N1CCNCC1)[C@@H](C)O FQWQZEXQOXIWIG-CYBMUJFWSA-N 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000004419 alkynylene group Chemical group 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 230000001747 exhibiting effect Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- XJMBEACZDGHGHJ-GFCCVEGCSA-N (1R)-1-[8-(propan-2-ylamino)-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol Chemical compound C(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC1=NC=2CCNCC=2C=C1)[C@@H](C)O XJMBEACZDGHGHJ-GFCCVEGCSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
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- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims 5
- ORPBOCVOGQKZHG-WBVHZDCISA-N (1R)-1-[2-[[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino]-8-[[(3S)-oxan-3-yl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol Chemical compound CN1CCN(CC1)C1=CC=C(N=N1)NC=1N=CC2=C(N=1)C(=NC(=C2)[C@@H](C)O)N[C@@H]1COCCC1 ORPBOCVOGQKZHG-WBVHZDCISA-N 0.000 claims 1
- SOTMPDQUEYMXFW-VQIMIIECSA-N (1R)-1-[8-[[(3R)-oxan-3-yl]amino]-2-[[5-(piperazin-1-ylmethyl)pyridin-2-yl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol Chemical compound N1(CCNCC1)CC=1C=CC(=NC=1)NC=1N=CC2=C(N=1)C(=NC(=C2)[C@@H](C)O)N[C@H]1COCCC1 SOTMPDQUEYMXFW-VQIMIIECSA-N 0.000 claims 1
- SUFZISMOJBBXJL-UHFFFAOYSA-N 1-[6-[[6-(3-methyloxetan-3-yl)-8-(propan-2-ylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-2-one Chemical compound C(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC1=CC=C(C=N1)N1C(CNCC1)=O)C1(COC1)C SUFZISMOJBBXJL-UHFFFAOYSA-N 0.000 claims 1
- AYRCMAIHDUTQFR-OAHLLOKOSA-N 1-[6-[[6-[(3S)-oxolan-3-yl]-8-(propan-2-ylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-2-one Chemical compound C(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC1=CC=C(C=N1)N1C(CNCC1)=O)[C@H]1COCC1 AYRCMAIHDUTQFR-OAHLLOKOSA-N 0.000 claims 1
- OIEPFHZIJSMAFC-UHFFFAOYSA-N 1-[[6-[[6-(difluoromethyl)-8-[(4-methylcyclohexyl)amino]pyrido[3,4-d]pyrimidin-2-yl]amino]pyridin-3-yl]methyl]piperidine-4-carboxylic acid Chemical compound FC(C1=CC2=C(N=C(N=C2)NC2=CC=C(C=N2)CN2CCC(CC2)C(=O)O)C(=N1)NC1CCC(CC1)C)F OIEPFHZIJSMAFC-UHFFFAOYSA-N 0.000 claims 1
- UYOODRZRKIFXNH-OAHLLOKOSA-N 1-[[6-[[8-(tert-butylamino)-6-[(1R)-1-hydroxyethyl]pyrido[3,4-d]pyrimidin-2-yl]amino]pyridin-3-yl]methyl]piperidin-4-ol Chemical compound C(C)(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC1=CC=C(C=N1)CN1CCC(CC1)O)[C@@H](C)O UYOODRZRKIFXNH-OAHLLOKOSA-N 0.000 claims 1
- ABEPISGQECZITD-UHFFFAOYSA-N 2-[4-[[6-[[6-(oxolan-3-yl)-8-(propan-2-ylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound C(C)(C)NC1=NC(=CC2=C1N=C(N=C2)NC1=CC=C(C=N1)CN1CCN(CC1)CCO)C1COCC1 ABEPISGQECZITD-UHFFFAOYSA-N 0.000 claims 1
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- MIXODQAAOQHDTG-UHFFFAOYSA-N tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(Cl)N=N1 MIXODQAAOQHDTG-UHFFFAOYSA-N 0.000 description 1
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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| PCT/JP2016/065770 WO2016194831A1 (ja) | 2015-05-29 | 2016-05-27 | ピリド［３，４－ｄ］ピリミジン誘導体及びその薬学的に許容される塩 |
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| CA2987019A1 CA2987019A1 (en) | 2016-12-08 |
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| CA3043561C (en) * | 2016-11-28 | 2025-03-11 | Teijin Pharma Limited | PYRIDO[3,4-D]PYRIMIDINE DERIVATIVE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF |
| PT3546456T (pt) * | 2016-11-28 | 2022-02-28 | Teijin Pharma Ltd | Cristal de derivado da pirido[3,4-d]pirimidina ou seu solvato |
| CN107337634B (zh) * | 2017-08-28 | 2019-07-09 | 新发药业有限公司 | 一种阿贝西利中间体化合物的制备方法 |
| JP7100125B2 (ja) | 2017-10-27 | 2022-07-12 | フレゼニウス・カビ・オンコロジー・リミテッド | リボシクリブおよびその塩の改善された調製のためのプロセス |
| WO2019126559A1 (en) | 2017-12-20 | 2019-06-27 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| CA3085366A1 (en) * | 2017-12-22 | 2019-06-27 | Petra Pharma Corporation | Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors |
| EP3865488A4 (en) | 2018-12-19 | 2021-12-22 | Keythera (Suzhou) Pharmaceuticals Co. Ltd. | MACROCYCLIC COMPOUND AS CDK INHIBITOR, METHOD OF MANUFACTURING AND MEDICAL USE |
| TW202112767A (zh) | 2019-06-17 | 2021-04-01 | 美商佩特拉製藥公司 | 作為磷脂酸肌醇磷酸激酶抑制劑之胺基吡啶衍生物 |
| AR119493A1 (es) * | 2019-07-29 | 2021-12-22 | Servier Lab | Derivados de 3,6-diamino-piridazin-3-ilo, composiciones farmacéuticas que los contienen y sus usos como agentes proapoptóticos |
| WO2022037592A1 (zh) * | 2020-08-17 | 2022-02-24 | 南京明德新药研发有限公司 | 嘧啶并环类化合物 |
| GB202018412D0 (en) * | 2020-11-23 | 2021-01-06 | Exscientia Ltd | Malt-1 modulators ii |
| TW202237585A (zh) | 2020-11-27 | 2022-10-01 | 瑞士商瑞森製藥公司 | Ｃｄｋ抑制劑 |
| WO2022149057A1 (en) | 2021-01-05 | 2022-07-14 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
| CN116023367A (zh) * | 2021-10-25 | 2023-04-28 | 优领医药科技(香港)有限公司 | 含四氢呋喃多环类衍生物、其药学上可接受的盐及其制备方法和应用 |
| WO2023109959A1 (zh) * | 2021-12-16 | 2023-06-22 | 药捷安康(南京)科技股份有限公司 | Cdk9抑制剂及其用途 |
| CN116410189B (zh) * | 2021-12-30 | 2024-08-06 | 中国科学院上海药物研究所 | 一种嘧啶并吡啶类化合物及其药用组合物和应用 |
| WO2023155841A1 (zh) * | 2022-02-16 | 2023-08-24 | 南京明德新药研发有限公司 | 嘧啶并环类化合物的盐型、晶型 |
| WO2024020380A1 (en) * | 2022-07-18 | 2024-01-25 | Iambic Therapeutics, Inc. | Quinazoline compounds and methods of use |
| TW202509031A (zh) * | 2023-05-15 | 2025-03-01 | 美商阿列克希雅醫療公司 | Ｃｄｋ抑制劑萘啶化合物 |
| WO2025070601A1 (ja) * | 2023-09-27 | 2025-04-03 | 帝人ファーマ株式会社 | 関節リウマチ治療薬 |
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| PL220952B1 (pl) * | 2002-01-22 | 2016-01-29 | Warner Lambert Co | 2-(Pirydyn-2-yloamino)pirydo[2,3-d]pirymidyn-7-ony |
| ATE412650T1 (de) | 2003-07-11 | 2008-11-15 | Warner Lambert Co | Isethionat salz eines selektiven cdk4 inhibitors |
| JPWO2006008874A1 (ja) * | 2004-05-21 | 2008-05-01 | 萬有製薬株式会社 | アミノチアゾ−ル骨格を有するＣｄｋ４、６選択的阻害剤 |
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| PA8852901A1 (es) | 2008-12-22 | 2010-07-27 | Lilly Co Eli | Inhibidores de proteina cinasa |
| UY33226A (es) * | 2010-02-19 | 2011-09-30 | Novartis Ag | Compuestos de pirrolopirimidina deuterada como inhibidores de la cdk4/6 |
| GB201216017D0 (en) * | 2012-09-07 | 2012-10-24 | Cancer Rec Tech Ltd | Inhibitor compounds |
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